Alectinib Yields Favorable Results in Phase III Trials of ALK-Positive NSCLC

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RESULTS OF TWO separate phase III trials confirm the activity of alectinib (Alecensa) in the central nervous system (CNS) in patients with anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC). Results lend support for alectinib as the better first-line treatment option over crizotinib (Xalkori), the current standard of care. Both studies were presented at the European Society for Medical Oncology (ESMO) 2017 Congress. 

The first was a secondary analysis of the ALEX study in ALK-positive NSCLC patients with CNS metastasis at baseline, which showed that alectinib is superior to crizotinib as first-line treatment in controlling existing brain metastases and preventing the formation of new ones.1 The second study, ALUR, found that alectinib was superior to standard chemotherapy as a third-line treatment in ALK-positive NSCLC patients who had disease progression after platinum-based therapy and crizotinib.2

Fiona Blackhall, MD, PhD

Fiona Blackhall, MD, PhD

Commenting on the implications of both trials, ESMO spokesperson Fiona Blackhall, MD, PhD, of the University of Manchester and The Christie Hospital, Manchester, UK, said: “Patients with NSCLC have a high risk of CNS metastases. These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care.” 

ALEX Trial 

THE CNS IS THE MOST COMMON SITE of metastasis and disease progression in ALK-positive NSCLC, explained lead author of the ALEX report, Shirish Gadgeel, MD, of the University of Michigan, Ann Arbor. Previous studies have shown that 30% of patients with ALK-positive NSCLC have CNS metastasis at initial diagnosis,3 and the CNS is the first site of disease progression in about 50% of patients, he noted.4,5 

The primary results of ALEX were presented at the 2017 ASCO Annual Meeting and published in The New England Journal of Medicine.6 In the overall analysis of the trial, alectinib achieved significantly superior progression-free survival vs crizotinib in treatment-naive ALK-positive NSCLC, reducing the risk of disease progression or death by 53% (P < .001). 

“These CNS results, along with systemic results, consolidate alectinib as a new standard of care for ALK-positive NSCLC.”
— Shirish Gadgeel, MD

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At the ESMO meeting, Dr. Gadgeel presented the results of a secondary analysis of 122 patients (40% of the study population) who had CNS metastases at baseline. 

“Results suggest that alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib. Clearly this superiority against CNS metastases contributes to the overall efficacy of alectinib, limiting the morbidity both from these metastases and also from treatments such as whole-brain irradiation,” Dr. Gadgeel told listeners. 

The ALEX investigators randomized 303 patients with stage IIIB and IV ALK-positive NSCLC to receive either alectinib at 600 mg twice daily or crizotinib at 250 mg twice daily, and they were treated until disease progression or unacceptable toxicity. Patients with asymptomatic brain metastases were permitted to enroll. With or without CNS metastasis at baseline, all patients underwent brain imaging every 8 weeks. 

Baseline characteristics were similar to those in the primary analysis, with the exception of more males with CNS metastasis randomized to receive alectinib vs crizotinib. Forty percent of patients with CNS metastasis at baseline had received some treatment for brain metastases prior to study entry. 

Alectinib significantly improved progression-free survival both in patients with baseline CNS metastasis and those without, producing hazard ratios (HRs) of 0.40 and 0.51, respectively, vs crizotinib. Median progression-free survival was not yet reached with alectinib vs 7.4 months with crizotinib in patients with CNS metastases (P < .0001). 

Alectinib also achieved significantly improved progression-free survival compared with crizotinib in patients who received prior radiotherapy as well as those who did not (P = .0078 and P = .0041 for alectinib vs crizotinib, respectively). 

In addition, more patients with no baseline CNS metastases subsequently developed them in the crizotinib group compared with the alectinib group (38% vs 7%). 

Alectinib delayed the time to CNS progression in patients with and without CNS metastasis at baseline, according to a competing-risk analysis. At 12 months, in patients with CNS metastasis at baseline, 16% of those treated with alectinib vs 58% of crizotinib recipients had the CNS as the first site of disease progression. In those without CNS metastasis at baseline, only 4.6% of the alectinib group developed CNS metastasis at first disease progression vs 31% of the crizotinib group. Alectinib also delayed the time to disease progression in patients with or without prior radiotherapy. 

“Alectinib has superior CNS activity vs crizotinib in patients with CNS disease both with and without prior radiation therapy across multiple CNS endpoints in previously untreated, advanced ALK-positive NSCLC. Overall, these CNS results, along with systemic results, consolidate alectinib as a new standard of care for ALK-positive NSCLC,” Dr. Gadgeel stated. 

ALUR Trial 

THE PHASE III ALUR trial enrolled 107 patients with ALK-positive NSCLC and progressive disease after previous treatment with both platinum-based chemotherapy and crizotinib. The investigators randomized participants to receive treatment with alectinib at 600 mg twice daily vs chemotherapy (pemetrexed [Alimta] at 500 mg/ m2 every 3 weeks or docetaxel at 75 mg/m2 every 3 weeks) in a 2:1 ratio. Treatment was continued until death, progressive disease, or study withdrawal. Patients were allowed to cross over to alectinib if they had disease progression on crizotinib. 

“In the first-line setting, alectinib is superior to crizotinib. Before this trial, no studies had yet compared alectinib vs chemotherapy in patients treated with crizotinib.”
— Silvia Novello, MD, PhD

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“The standard of care for ALK-positive NSCLC is crizotinib. However, patients treated with first-line crizotinib have disease progression, most often in the CNS. In the first-line setting, alectinib is superior to crizotinib. Before this trial, no studies had yet compared alectinib vs chemotherapy in patients treated with crizotinib,” said senior author Silvia Novello, MD, PhD, of the University of Turin, Italy. 

The study met its primary endpoint: Median progression-free survival was 9.6 months in the alectinib arm vs 1.4 months in the chemotherapy arm (HR = 0.15, P < .001). A subgroup analysis of progression-free survival favored alectinib over crizotinib for all subgroups. 

The overall response rate was 37.5% in the alectinib arm vs 2.9% in the chemotherapy arm, according to an independent review. The disease control rate was 80.6% with alectinib vs 28.6% with chemotherapy. 

“In the safety analysis, keep in mind the median time on treatment: 20 weeks with alectinib vs 6 weeks with chemotherapy,” Dr. Novello said. 

Grade 3 to 5 adverse events occurred in 27.1% of those who received alectinib vs 41.2% of chemotherapy recipients. Adverse events leading to treatment discontinuation occurred in 5.7% vs 8.8% of the two arms, respectively. More dose interruptions and reductions were reported in the chemotherapy arm. Chemotherapy-treated patients had higher rates of adverse events occurring in at least 10% of patients. 

“These results support alectinib as a new standard of care for patients with previously treated ALK-positive NSCLC,” Dr. Novello stated. 

DISCLOSURE: Dr. Blackhall has received speaker honoraria and research funding from Pfizer, Boehringer Ingelheim, Novartis, and AstraZeneca. Dr. Gadgeel has received consulting fees from Boehringer Ingelheim, ARIAD, Novartis, Genentech, Pfizer, and AstraZeneca. Dr. Novello is on the speakers bureau for Eli Lilly, BMS, MSD, AstraZeneca, and Roche. 


1. Gadgeel S, Peters S, Mok T, et al: Alectinib vs crizotinib in treatment-naive ALK+ NSCLC: CNS efficacy results from the ALEX study. ESMO 2017 Congress. Abstract 1298O_PR. Presented September 11, 2017. 

2. Wolf J, Mazieres J, Oh I-J, et al: Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer. ESMO 2017 Congress. Abstract 1299O_PR. Presented September 11, 2017. 

3. Johung KL, Yeh N, Desai NB, et al: Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol 34:123-129, 2016. 

4. Weickhardt AJ, Scheier B, Burke JM, et al: Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 7:1807-1814. 

5. Yoshida T, Oya Y, Tanaka K, et al: Clinical impact of crizotinib on central nervous system progression in ALK-postive non-small lung cancer. Lung Cancer 97:43-47, 2016. 

6. Peters S, Camidge DR, Shaw AT, et al: Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377:829-838, 2017.

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